Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression

Abstract

BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is a multi-faceted protein-modulating cell -cell and cell -matrix interactions. In cancer, SPARC can be not only associated with a highly aggressive phenotype, but also acts as a tumour suppressor. The aim of this study was to characterise the function of SPARC and its modulation by fibroblast growth factor receptor (FGFR) 1 isoforms in pancreatic ductal adenocarcinoma (PDAC). METHODS AND RESULTS: Exogenous SPARC inhibited growth, movement, and migration. ShRNA inhibition of endogenous SPARC in ASPC-1 and PANC-1 cells resulted in increased anchorage-dependent and -independent growth, transwell migration, and xenograft growth as well as increased mitogenic efficacy of fibroblast growth factor (FGF) 1 and FGF2. Endogenous SPARC expression in PANC-1 cells was increased in FGFR1-IIIb over-expressing cells, but decreased in FGFR1-IIIc over-expressing cells. The up-regulation of endogenous SPARC was abrogated by the p38-mitogen-activated protein kinase inhibitor SB203580. SPARC was detectable in conditioned medium of pancreatic stellate cells (PSCs), but not PDAC cells. Conditioned medium of PDAC cells reduced endogenous SPARC expression of PSCs. CONCLUSION: Endogenous SPARC inhibits the malignant phenotype of PDAC cells and may, therefore, act as a tumour suppressor in PDAC. Endogenous SPARC expression can be modulated by FGFR1-III isoform expression. In addition, PDAC cells may inhibit endogenous SPARC expression in surrounding PSCs by paracrine actions.

Aberrant methylation of secreted protein, acidic and rich in cysteine in human laryngeal and hypopharyngeal carcinoma

“…On the other hand, the inactivation of SPARC by aberrant DNA methylation has also been reported in pancreatic, ovarian, colon and lung cancers (9,11,12,22). With regards to SPARC function, exogenous SPARC inhibits the proliferation, movement and migration of human cancer cell lines (11,23), which is consistent with the results of an in vivo study (14). A recent study also provided evidence that exogenous SPARC enhances the apoptosis of colon cancer cells via the caspase 8 pathway (24).…”

Novel Role for Matricellular Proteins in the Regulation of Islet β Cell Survival

“…There is strong evidence that SPARC is important in the development of pancreatic cancer (15)(16)(17)(18)(19)(20)(21)(22). However, the precise effects of SPARC are cell type dependent, and the effect of SPARC on the growth and survival of islet ␤ cells has not previously been examined.…”

Pancreatic Cancer: The Role of Pancreatic Stellate Cells in Tumor Progression

“…High SPARC expression in the stroma was correlated with a less favorable prognosis [37,38]. Recent data by Mantoni et al [38] and Chen et al [39] have demonstrated that PSCs express higher levels of SPARC than pancreatic cancer cells, and that SPARC could be detected in the conditioned medium of PSCs [39]. However, the precise function of SPARC in PDAC progression remains conjectural.…”